Autistic feature as a presentation of Inborn Errors of Metabolism

Autism spectrum disorder (ASD) is a category of neurodevelopmental disorders characterized by social and communication impairment and restricted or repetitive behaviors. The pathogenesis of ASD is not well understood and it’s proved that genetic is strongly associated with ASD in 5 to 25% of cases. Inborn errors of metabolism(IEMs), defined by a vast array of disorders that are caused by specific enzyme deficiencies or transport protein defects, is as frequent as in 1 in 800 births. IEMs can manifest several psychiatric or behavioral manifestations such as self-injuriesincreased activity and aggression, personality changes, paranoia, depression, catatonia, and psychosis. IEMs underlie autistic symptoms in less than 5% of cases. The literature on the association between ASD and respiratory chain abnormalities is growing, including complex III/IV deficiency and MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, as well as glucose-6-phosphate dehydrogenase deficiency. Google Scholar, Pubmed, and SCOPUS databases were searched using a combination of the following keywords: “autism spectrum disorder”, “autism spectrum”, “autistic feature” and “inborn error of metabolism”, “ IEM”, “congenital error of metabolism”. Initially, 655 articles were found and our expert and methodologist altogether selected 187 articles based on the titles, relevance, and text language. After reading full texts, 37 studies were selected for review. We think it’s best to consider IEMs in children with syndromic ASD and/or if there is a strong familial history of autism or parental consanguineous marriage.

ASD is more common in boys than girls (a male/ female ratio of 4.2)(4) and happens in nearly 10% of an ASD patient's siblings. (5) The pathogenesis of ASD is not well studied and a strong genetic caustic association is found at 5 to 25 percent of cases. ( IEMs can manifest several psychiatric or behavioral manifestations such as self-injuries-increased activity and aggression, personality changes, paranoia, depression, catatonia, and psychosis. (15) IEMs cause the autistic features in less than 5% The current study aimed to narratively review the associated metabolic conditions in ASD children with or without any previous condition.

Methodology
Google Scholar, PubMed, and SCOPUS databases were searched using the combinations of following keywords: "autism spectrum disorder", "autism spectrum", "autistic feature", "inborn error of metabolism", " IEM", and "congenital error of metabolism". Initially, 655 articles were found and our expert and methodologist altogether selected 187 articles based on the correlation of titles and text language. After reading the abstract and full texts, a total of 49 studies were selected for review.
The inclusion and exclusion criteria are shown in Table 1.

Associated disorders
We classified metabolic disorders that manifested autistic features in 10 groups (table 2).

Amino acid metabolism
Autistic behavior has been in imbalances in neurotransmitter amines function such as dopamine, noradrenaline, and serotonin. Hyperserotonemia in particular shows a familial pattern and was found in over 25% of children and adolescents with autism. Amino acids can act as neurotransmitters in the central nervous system(CNS). In particular, glutamate, which can have an excitatory effect at high concentrations. (18,19) A study by Aldred

Methionine, Cysteine, and Homocysteine
The methionine-folate pathway defect have been identified in individuals with ASD. As a pathway that plays a critical role in DNA synthesis, methylation, and cellular redox balance, folate deficiency has been known as a plausible predictor for neurodegenerative diseases, such as Parkinson's disease and Alzheimer's. (11,22) Methionine is an essential amino acid that is later converted S-adenosyl-methionine(SAM) and acts as the body's main methyl group donor.

Mitochondrial & Fatty acid metabolism disorders
The mitochondria is an intracellular organelle that plays a crucial role in adenosine 5′-triphosphate CTD is a known X-linked IEM that causes by mutations in creatine transporter gene (SLC8A8).
It can cause disturbance of creatine import into the cells and cause problems in organs that require large amounts of energy such as the brain.
Intellectual disability (ID), epilepsy, and autistic behavior and language disability are its main clinical presentations (34

Androgen theory of autism
The androgen theory of autism proposes that autism spectrum conditions (ASC) are in part due to elevated fetal testosterone (FT) levels.
Significantly higher male to female ratio sparked the idea that the autistic brain might be an "extreme" of the typical male brain. Increased It also argued that elevated testosterone level is a common risk factor for hyperandrogenism in adult women and those with autism, rather than any of the conditions such as hirsutism causing autism.

Inclusion criteria Exclusion criteria
Articles that were about IEMs of metabolism, autism, and other matters of interest to the authors Any language other than English Availability of full text or abstract Articles before 2009/ If the chronological view isn't reviewed    (Table 3)